Regular Transfusions Research Articles

Beta Thalassemia in Children: Established Approaches, Old Issues, New Non-Curative Therapies, and Perspectives on Healing.

Despite a decrease in prevalence and incidence rates, beta thalassemia continues to represent a significant public health challenge worldwide. In high-resource settings, children with thalassemia have an open prognosis, with a high chance of reaching adulthood and old age with a good quality of life. This is achievable if transfusion therapy is properly managed, effectively mitigating ineffective erythropoiesis and its associated complications while also minimizing excessive iron accumulation. Adequate iron chelation is essential to maintain reactive forms of iron within the normal range throughout life, thus preventing organ damage caused by hemosiderosis, which inevitably results from a regular transfusion regimen. New therapies, both curative, such as gene therapy, and non-curative, such as modulators of erythropoiesis, are becoming available for patients with transfusion-dependent beta thalassemia. Two curative approaches based on gene therapy have been investigated in both adults and children with thalassemia. The first approach uses a lentivirus to correct the genetic defect, delivering a functional gene copy to the patient's cells. The second approach employs CRISPR/Cas9 gene editing to directly modify the defective gene at the molecular level. No non-curative therapies have received approval for pediatric use. Among adults, the only available drug is luspatercept, which is currently undergoing clinical trials in pediatric populations. However, in many countries around the world, the new therapeutic options remain a mirage, and even transfusion therapy itself is not guaranteed for most patients, while the choice of iron chelation therapy depends on drug availability and affordability.

Cardiovascular magnetic resonance in β-thalassemia major: beyond T2.

Β-thalassemia major (TM) patients underwent regular transfusions to prevent complications of chronic anemia. However, these regular transfusions result in progressive iron accumulation in vital organs, including the heart. Myocardial iron overload can lead to cardiac dysfunction and ultimately to heart failure. Diagnosis of cardiac dysfunction in β-TM patients is usually made through clinical examination, electrocardiogram, and echocardiography. Cardiac magnetic resonance (CMR), through the measurement of T2* relaxation time, represents the diagnostic modality of choice for assessing myocardial iron overload and guiding the iron chelation therapy. Despite a tailored chelation therapy reducing myocardial iron overload, heart failure remains the leading cause of morbidity and mortality even in well-treated β-TM patients. Advances in CMR, including myocardial strain, parametric mapping (T1, T2, and extracellular volume), and late gadolinium enhancement (LGE) measurements, have expanded its role in the diagnosis, prognosis, and follow-up of these patients. This review seeks to offer a thorough overview of the potential uses of CMR in β-TM, extending beyond the established role of T2* measurement in guiding chelation therapy. It delves into the emerging applications of new CMR imaging biomarkers that could improve the overall management of β-TM patients.

Clinical Burden and Healthcare Resource Utilization Associated With Managing Transfusion-dependent β-Thalassemia in England

PurposePatients with transfusion-dependent β-thalassemia (TDT) have reduced levels of β-globin, leading to ineffective erythropoiesis and iron overload. Patients with TDT depend on regular red blood cell transfusions (RBCTs) and iron chelation therapy for survival and management of disease- and treatment-related clinical complications. This study describes the clinical and economic burden in patients with TDT in England. MethodsThis longitudinal, retrospective study linked the Clinical Practice Research Datalink (CPRD) database with secondary care data from the Hospital Episode Statistics database to identify patients with a diagnosis of β-thalassemia between July 1, 2008, and June 30, 2018. Included patients had a diagnosis of β-thalassemia prior to the index date, ≥8 RBCTs per year for ≥2 consecutive years, and ≥1 year of follow-up data available from the index date. Each eligible patient was exact matched with up to 5 controls in the CPRD. Proportions of deaths and rates of mortality, acute and chronic complications, and healthcare resource utilization (HCRU) were calculated during the follow-up period. FindingsOf 11,359 identified patients with β-thalassemia, 237 patients with TDT met the eligibility criteria and were matched with 1184 controls. The mean age at the index date was approximately 25 years in the patient and control groups. The proportion of deaths (7.17% vs 1.18%; P < 0.05) and mortality rate (1.19 deaths per 100 person-years vs 0.20 deaths per 100 person-years) were higher among patients with TDT compared to controls. Endocrine complications and bone disorders were the most prevalent complications among patients with TDT (58.23%) and included osteoporosis (29.11%), diabetes mellitus (28.27%), and hypopituitarism (28.27%). Patients with TDT had a mean of 13.62 RBCTs per patient per year (PPPY). HCRU was substantially higher among patients with TDT, wherein patients with TDT had higher rates of prescriptions recorded in primary care (24.09 vs 8.61 PPPY), outpatient visits (16.69 vs 1.31 PPPY), and inpatient hospitalizations (17.41 vs 0.24 PPPY) than controls. Inpatient hospitalizations were primarily <1 day, with 16.62 events PPPY lasting <1 day and 0.79 events PPPY lasting ≥1 day. Patients with TDT aged ≥18 years had increased rates of mortality, clinical complications, and HCRU than those aged <18 years. ImplicationsPatients with TDT in England have higher mortality than matched controls, substantial disease-related clinical complications, and substantial HCRU. High mortality and clinical complications highlight the need for additional innovative therapies for TDT.

Impact of HbE mutation on the clinical severity of HbH disease: Amulticentre study from Thailand.

Haemoglobin (Hb) H disease and HbH disease with co-inherited HbE mutation are the most prevalent forms of α-thalassaemia in Southeast Asia. Data were limited when comparing clinical phenotypes between these two patient groups. We conducted a Thai multicentre study and enrolled 588 patients [median (IQR) age 13.0 (6.7-20.3) years], including those with deletional HbH disease with (n = 47) and without (n = 187) co-inherited HbE mutation and non-deletional HbH disease with (n = 101) and without (n = 253) co-inherited HbE mutation. Patients with HbH disease with co-inherited HbE mutation suffered more severe manifestations than those without. This observation was more pronounced in patients with non-deletional HbH disease. A greater proportion of patients with non-deletional HbH disease with co-inherited HbE mutation (43.6%) eventually required regular transfusions compared to those without (30.4%, p = 0.019). Among those with non-deletional HbH disease who did not require regular transfusions, Hb levels were lower in patients with co-inherited HbE mutation [8.1 (7.2-8.6) vs. 8.8 (8.2-9.5) g/dL, p < 0.001]. Among patients requiring regular transfusions who underwent splenectomy, 11/12 patients with non-deletional HbH disease stopped transfusion compared with 1/3 in non-deletional HbH disease with co-inherited HbE mutation group (p = 0.024). These findings provide insights for the clinical monitoring and management of HbH disease in the region.

Plasma sphingomyelin levels were negatively correlated with ferritin levels in splenectomized thalassemia patients

Abstract Beta thalassemia results from decreased production of beta chains due to either mutations or deletions in the beta-globin gene, leading to impaired production of hemoglobin A. Thalassemia patients take frequent blood transfusions to compensate for hemolytic anemia and iron overload. Iron overload is monitored by serum ferritin levels in these patients. Extra-medullary hematopoiesis in beta thalassemia major leads to hypersplenism which often necessitates splenectomy to increase red cell life span and decrease transfusion need. Sphingomyelin is the second most abundant phospholipid in human plasma after phosphatidylcholine. In contrast to the well-defined roles of sphingolipids in cell membranes, their possible physiological role in lipoprotein metabolism has recently gained attention. Increased circulating levels of sphingomyelins and ceramides were observed in obesity, diabetes, and cardiovascular diseases. Although lipid abnormalities such as hypocholesterolemia and relatively increased triglycerides were reported in beta-thalassemia patients, there is no study investigating sphingolipid levels in thalassemia. Therefore, we investigate certain long chain and very long chain sphingomyelins and ceramides in beta-thalassemia patients who are under routine follow-up in our hospital. Thalassemia major patients who applied to the hospital for regular blood transfusion and gave consent were included in the study. Blood samples were obtained before transfusion. Plasma sphingomyelin (C16, C18 and C24) and ceramide (C16, C18, C20, C22, C24) species were measured by triple quadruple LC-ESI-MS/MS (Shimadzu, Japan). D-erythrosphingosine-D9 (Matreya) was used as an internal standard, all other lipid standards were from Avanti. Body iron stores of the patients were monitored by serum ferritin levels. A total of thirty patients were included in the study. All patients typically received regular erythrocyte suspension transfusions every three weeks and continuous oral iron chelation therapy. Twenty of the patients had a previous splenectomy. The mean age was 34.5 ±8.1 years in the splenectomy group and 32.8 ±8 years in the group without splenectomy. Mean ferritin levels were not different between the groups, being 1073.2±563.5 µg/L in splenectomy and 1709 ±1660.4 µg/L in non-splenectomy groups. All measured sphingolipid levels were similar between splenectomy and non-splenectomy groups. When correlation analysis was performed between measured sphingolipid and ferritin levels, significant negative correlations were found between sphingomyelin C16 (r= -0.591 p&amp;lt;0.006) and C18 (r= -0.594 p&amp;lt;0.006) with ferritin levels in the splenectomy group. However, this negative correlation was absent in the non-splenectomy group. In conclusion, we found that iron overload is associated with lower plasma sphingomyelin levels in splenectomized thalassemia patients. We have been working on the lipidomic analysis of the plasma and erythrocytes of thalassemia patients and other hemolytic anemias. The results may further help to get a better picture of lipid metabolism in thalassemia.

Early Detection of Myocardial Involvement in Thalassemia Intermedia Patients: Multiparametric Mapping by Magnetic Resonance Imaging.

No study has assessed myocardial T1 and T2 values in patients with beta-thalassemia intermedia (β-TI). To assess the prevalence of myocardial involvement in β-TI patients by T2* relaxometry and native T1 and T2 mapping and to determine the correlation of myocardial relaxation times with demographic and clinical parameters. Prospective matched-cohort study. 42 β-TI patients (27 females, 39.65 ± 12.32 years), enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 42 age- and sex-matched healthy volunteers (27 females, 40.01 ± 11.36 years) and thalassemia major (TM) patients (27 females, 39.27 ± 11.57 years). 1.5 T/multi-echo gradient echo, modified Look-Locker inversion recovery, multi-echo fast-spin-echo, cine balanced steady-state-free precession, and late gadolinium enhancement (LGE) sequences. Hepatic, pancreatic, and left ventricular (LV) T2* values, LV native T1 and T2 values, biventricular ejection fractions and volumes, and presence and extent of replacement myocardial fibrosis. Comparisons between two groups were performed with two-sample t tests, Wilcoxon's signed rank tests, or χ2 testing. Correlation analysis was performed using Pearson's or Spearman's test. P < 0.05 was considered statistically significant. β-TI patients had significantly higher LV T2 values than healthy subjects (56.84 ± 4.03 vs. 52.46 ± 2.50 msec, P < 0.0001) and significantly higher LV T1 values than TM patients (1018.32 ± 48.94 vs. 966.66 ± 66.47 msec, P < 0.0001). In β-TI, female gender was associated with significantly increased LV T1 (P = 0.041) and T2 values (P < 0.0001), while splenectomy and presence of regular transfusions were associated with significantly lower LV T1 values (P = 0.014 and P = 0.001, respectively). In β-TI patients, all LV relaxation times were significantly correlated with each other (T2*-T1: P = 0.003; T2*-T2: P = 0.003; T1-T2: P < 0.0001). Two patients with a reduced LV T2* also had a reduced LV T1, while only one had a reduced LV T2. Three patients had a reduced LV T1 but a normal LV T2*; 66.7% of the patients had an increased LV T2. All LV relaxation times were significantly correlated with pancreas T2* values (T2*: P = 0.033; T1: P < 0.0001; T2: P = 0.014). No LV relaxation time was associated (P > 0.05) with hepatic iron concentration, biventricular function parameters, or LGE presence. The combined use of all three myocardial relaxation times has potential to improve sensitivity in the detection of early/subclinical myocardial involvement in β-Tl patients. 2 TECHNICAL EFFICACY: Stage 2.

Hb SKMC and an unprecedented γδβ-thalassemia: first report from Iraq

ABSTRACT Background Thalassemias are genetic disorders of globin chain synthesis. In Iraq, β-thalassemia is more prevalent than α-thalassemia. This study identifies two unpredicted globin gene mutations, a rare α-globin gene mutation (Hb SKMC) and a novel γδβ-thalassemia deletion. Methods Over 2 years, the Genetics unit at PAR hospital in Erbil, northern Iraq processed 137 β-thalassemia and 97 α-thalassemia genetic testing requests. Three symptomatic thalassemia cases with unreported genotypes were identified. Proband-1α and proband-2α had Hb H disease, while proband-1β had severe transfusion-dependent β-thalassemia (TDT). Molecular studies included multiplex PCR, reverse hybridization, multiplex ligation-dependent probe amplification (MLPA), and globin gene sequencing. Results The α-thalassemia probands exhibited moderate microcytic hypochromic anemia with irregular transfusions and splenomegaly. Hb H disease was confirmed by positive Hb H tests and high-performance liquid chromatography (HPLC). Molecular analysis revealed heterozygous –MED deletion in proband-1α and α2Poly-A2 mutation in proband-2α. Sequencing identified the Hb SKMC (HBA1:c.283_300+3dup) mutation in both probands. The β-thalassemia proband showed anemia and regular transfusions. Molecular studies detected the IVS1.110 G>A mutation and a novel γδβ-thalassemia deletion in compound heterozygous form. The maternal sample showed the IVS1.110 G>A mutation, and MLPA confirmed the γδβ-thalassemia deletion in the paternal sample. Conclusion These findings highlight the genetic diversity of thalassemias in the region and emphasize the importance of advanced molecular diagnostics in detecting rare mutations.

Magnetic Resonance Evaluation of Tissue Iron Deposition and Cardiac Function in Adult Regularly Transfused Thalassemia Intermedia Compared with Thalassemia Major Patients.

Objectives: This multicenter, retrospective, population-based, matched-cohort study compared clinical characteristics and magnetic resonance imaging (MRI) findings, including hepatic, pancreatic, and cardiac iron levels and cardiac function, between 135 adult regularly transfused thalassemia intermedia (TI) patients (44.73 ± 12.16 years, 77 females) and 135 age- and sex-matched thalassemia major (TM) patients (43.35 ± 9.83 years, 77 females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Methods: The MRI protocol included the quantification of hepatic, pancreatic, and cardiac iron levels (R2* technique), the assessment of biventricular function parameters (cine images), and the detection of replacement myocardial fibrosis (late gadolinium enhancement technique). Results: Age, sex, frequency of splenectomy and chelation, and serum ferritin levels were not significantly different (p > 0.05) between the two groups, but TI patients started regular transfusions significantly later (p < 0.0001) and showed significantly lower pre-transfusion hemoglobin levels (p = 0.005). No difference was found in hepatic iron levels (p = 0.853). TI patients exhibited significantly lower pancreatic R2* values (p < 0.0001), also correcting for the duration of regular transfusions, and significantly lower cardiac R2* values (p < 0.0001). In the receiver operating characteristic analysis, pancreatic iron was the strongest discriminator between the two diseases. Left and right ventricular end-diastolic volume indexes were significantly higher in TI than in TM patients (p = 0.003 and p = 0.046, respectively), but the correction for the duration of regular transfusions removed the disease-specific differences (p > 0.05). Left ventricular (LV) mass index was significantly higher in TI (p = 0.049), while no difference (p > 0.05) was found in biventricular ejection fractions and replacement myocardial fibrosis. Conclusions: TI patients showed lower pancreatic and cardiac iron burden and more pronounced LV hypertrophy. These differences could not be explained by the different duration of the transfusional regimen.

Prevention of Blood Incompatibility Related Hemagglutination: Blocking of Antigen A on Red Blood Cells Using In Silico Designed Recombinant Anti-A scFv.

Critical blood shortages plague healthcare systems, particularly in lower-income and middle-income countries. This affects patients requiring regular transfusions and creates challenges during emergencies where universal blood is vital. To address these shortages and support blood banks during emergencies, this study reports a method for increasing the compatibility of blood group A red blood cells (RBCs) by blocking surface antigen-A using anti-A single chain fragment variable (scFv). To enhance stability, the scFv was first modified with the addition of interdomain disulfide bonds. The most effective location for this modification was found to be H44-L232 of mutant-1a scFv. ScFv was then produced from E.coli BL21(DE3) and purified using a three-step process. Purified scFvs were then used to block maximum number of antigens-A on RBCs, and it was found that only monomers were functional, while dimers formed through incorrect domain-swapping were non-functional. These antigen-blocked RBCs displayed no clumping in hemagglutination testing with incompatible blood plasma. The dissociation constant KD was found to be 0.724 μM. Antigen-blocked RBCs have the potential to be given to other blood groups during emergencies. This innovative approach could significantly increase the pool of usable blood, potentially saving countless lives.

Regulatory Assessment of Casgevy for the Treatment of Transfusion-Dependent β-Thalassemia and Sickle Cell Disease with Recurrent Vaso-Occlusive Crises.

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are hereditary haemoglobinopathies characterized by a reduction in functional β-globin chains. Both conditions cause tiredness and increase susceptibility to infection, which can lead organ failure, significantly reducing life expectancy and typically requiring those affected to undergo regular erythrocyte transfusion. Recently, a novel therapeutic treatment for SCD and TDT was approved by the UK regulatory body (Medicines and Healthcare products Regulatory Agency; MHRA). Exagamglogene autotemcel (Casgevy) is the first licensed therapy globally to utilize CRIPSR/Cas9 technology and induces an increase in expression of γ-globin chains to compensate for the reduction in functional β-globin. Casgevy represents a first-in-class therapeutic, and numerous considerations were made by the MHRA throughout its assessment of the medicine. These include, but are not limited to, the risk of tumorigenicity and off-target editing, a limited cohort size, the validity of proposed dosing and the conduction of only single-arm studies. The MHRA's analyses of the data to support the proposed indications are presented and discussed throughout this manuscript. Overall, the sponsors claims were considered well supported by their data, and Casgevy was licensed for the treatment of TDT or SCD in patients 12 years of age and older for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen-matched related HSC donor is not available.

Correlation between plasma biochemical parameters and cardio-hepatic iron deposition in thalassemia major patients

Introduction Major Thalassemia patients suffer from iron overload and organ damage, especially heart and liver damage. Early diagnosis and treatment with a chelator can reduce the complications and mortality of iron overload. Therefore, we aimed to investigate the biochemical and hematological predictors as an alternative and indirect indicator of iron deposition in heart and liver cells in comparison with the MRI T2* method as the gold standard. Material and method MRI T2* was evaluated in the heart and liver tissues of 62 major beta-thalassemia patients undergoing regular transfusion and chelator therapy. Biochemical and hematological factors were also measured, including serum ferritin, serum electrolytes, liver enzymes, hemoglobin, blood glucose, and serum magnesium. The correlation between these factors was assessed using statistical evaluations. Result Serum ferritin had a positive and significant correlation with liver siderosis based on MRI T2* (p-value = .015), and no significant association was observed with cardiac siderosis (p-value = .79). However, there was a significant positive correlation between cardiac iron deposition and fasting blood sugar level (p-value = −.049), and plasma level of liver enzymes (alanine aminotransferase (ALT) (p-value = .001), aspartate aminotransferase (AST ((p-value = .01)). Moreover, there was a significant negative correlation between cardiac iron overload and plasma magnesium level (p-value = .014). According to MRI T2*, there was no significant correlation between cardiac and hepatic iron overload (p value = .36). Conclusion An increase in blood sugar or liver enzymes and a decrease in serum magnesium was associated with an increase in cardiac iron overload based on MRI T2*. Liver iron overload based on MRI T2* had a significant correlation with serum ferritin.

Obstetric and Gynecology Department of RSUD dr. Soedono Provinsi Jawa

Anaemia is a condition in which the number of red blood cells or the haemoglobin concentration within them is lower than normal. Thalassemia is a Mutation of the globin gene can cause changes in the globin chain, e.g. structural haemoglobinopathy or changes in the rate of synthesis or the production ability of certain globin chains. Epidemiological research in Indonesia found that the frequency of the beta thalassemia gene ranges from 3-10%. Case report of patient Mrs. T, 27 years old, HPHT: 01-10-2023, routine ANC examination every month, ANC examination results 18-19 weeks no complaints and laboratory examination results Hb 4.7. Patients with thalassemia beta major and intermediate need to be given regular transfusions and kept their hemoglobin levels above 10 mg/dl. All patients with homozygous thalassaemia should receive folic acid supplements.

Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life

Transfusion-dependent thalassemia (TDT) is a major public health concern in India, requiring regular transfusions for survival. There is also significant morbidity caused by iron overload and transfusion related infections. Novel therapies targeting fetal hemoglobin induction are the need of the hour in resource-poor institutions for patients where transplant is not feasible for various reasons. This single arm, non-randomised prospective trial evaluated the efficacy and safety of a combination of low dose thalidomide and hydroxyurea in TDT along with the impact on quality of life (QoL). It included 41 TDT patients, who failed a reasonable trial of hydroxyurea. Complete response (CR) was defined as transfusion independence and partial response (PR) denoted at least a 50% reduction in transfusion requirement. The rest were defined as non-responders (NR). The mean age of the cohort was 20.78 years (range 12–45 years). There were 13 males and 28 females. Nineteen (46.3%), 7 (17.1%), and 15 (36.6%) patients achieved CR, PR, and no response respectively. The overall response rate (CR + PR) was 63.4%. There was a significant increase in hemoglobin levels with decrement in transfusion burden and ferritin levels. There were no significant adverse reactions. No significant predictors of response were found including amongst genetic modifiers. It improved the health related QoL amongst responders. The combination of thalidomide and hydroxyurea appear safe and effective in the reduction in transfusion requirement of TDT patients. The judicious use of these drugs can improve the quality of life and pave the way for patients not eligible for a stem cell transplant.

Multiparametric cardiac magnetic resonance in patients with thalassemia intermedia: new insights from the E-MIOT network.

In a relatively large cohort of thalassemia intermedia (TI) patients, we systematically investigated myocardial iron overload (MIO), function, and replacement fibrosis using cardiac magnetic resonance (CMR), we assessed the clinical determinants of global heart T2* values, and we explored the association between multiparametric CMR findings and cardiac complications. We considered 254 beta-TI patients (43.14 ± 13.69years, 138 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. MIO was quantified by T2* technique and biventricular function and atrial areas by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Compared to never/sporadically transfused patients, regularly transfused (RT)-TI patients exhibited significantly lower global heart T2* values, biventricular end-diastolic volume indexes, left ventricular mass index, and cardiac index. In RT-TI patients, age and serum ferritin levels were the strongest predictors of global heart T2* values. Independently from the transfusional state, cardiac T2* values were not associated with biventricular function. Of the 103 (40.6%) patients in whom the contrast medium was administrated, 27 (26.2%) had replacement myocardial fibrosis. Age, sex distribution, cardiac iron, and biventricular function parameters were comparable between patients without and without replacement myocardial fibrosis. Twenty-five (9.8%) patients had a history of cardiac complications (heart failure and arrhythmias). Increased age and replacement myocardial fibrosis emerged as significant risk markers for cardiac complications. In TI, regular transfusions are associated with less pronounced cardiac remodeling but increase the risk of MIO. Replacement myocardial fibrosis is a frequent finding associated with cardiac complications.

Survival and causes of death in patients with alpha and beta-thalassemia in Northern Thailand

Background Thalassemia is the most prevalent hereditary anaemia worldwide. Severe forms of thalassemia can lead to reduced life expectancy due to disease-related complications. Objectives To investigate the survival of thalassemia patients across varying disease severity, causes of death and related clinical factors. Patients and methods We conducted a retrospective review of thalassemia patients who received medical care at Chiang Mai University Hospital. The analysis focused on survival outcomes, and potential associations between clinical factors and patient survival. Results A total of 789 patients were included in our study cohort. Among them, 38.1% had Hb H disease, 35.4% had Hb E/beta-thalassemia and 26.5% had beta-thalassemia major. Half of the patients (50.1%) required regular transfusions. Sixty-five patients (8.2%) had deceased. The predominant causes of mortality were infection-related (36.9%) and cardiac complications (27.7%). Transfusion-dependent thalassemia (TDT) (adjusted HR 3.68, 95% CI 1.39–9.72, p = 0.008) and a mean serum ferritin level ≥3000 ng/mL (adjusted HR 4.18, 95% CI 2.20–7.92, p < 0.001) were independently associated with poorer survival. Conclusions Our study highlights the primary contributors to mortality in patients with thalassemia as infection-related issues and cardiac complications. It also underscores the significant impact of TDT and elevated serum ferritin levels on the survival of thalassemia patients.

Current challenges of blood transfusions in patients with thalassemia in India and future perspectives

The introduction of regular red blood cell transfusions transformed thalassemia major from a fatal childhood disease into a chronic disorder. Thalassemia is highly prevalent in South Asia, including the Indian subcontinent, and blood transfusion remains the cornerstone of management for these patients. But safe blood transfusions still remain a major problem in India. Difficulties in maintaining adequate blood inventory, a lack of a national blood act, and fragmented blood transfusion services are some of the major contributing factors for the delay in blood supply. In most of the blood centers, alloantibody detection facilities and extended red cell antigen typing are unavailable. Awareness is the key to reducing alloimmunization, which limits the effectiveness of transfusions and the potential availability of blood. Patients with thalassemia are also at high risk of transfusion-transmitted infections unless appropriate blood screening is in place. Hence, many patients remain under-transfused, resulting in decreased health and quality-of-life outcomes. Facilities such as leucoreduction and immunohematological monitoring following a blood transfusion are often lacking in India, especially at the sub-district level. Continuous efforts to raise community awareness, regular training of health-care workers, and proper utilization of available resources are essential to ensuring safe blood transfusions for patients with thalassemia. Access to the new treatments at an affordable cost may reduce the blood transfusion burden for thalassemia patients in India.

Mitapivat: New dawn in pyruvate kinase deficiency and beyond

Mitapivat is the first in class oral allosteric activator of pyruvate kinase enzyme, leading to increased ATP production. Since red blood cells (RBC) rely on anaerobic metabolism, converting phosphoenolpyruvate to pyruvate in Embden– Meyerhof glycolytic pathway is the most important step for ATP production. Deficiency of ATP in patients with pyruvate kinase deficiency (PKD) leads to the destruction of RBCs. In hemoglobinopathies, including thalassemia and sickle cell disease, increased stress and utilization leads to rapid depletion of ATP resources.Phase II DRIVE PK study was the first randomized controlled trial that showed benefits in adult patients without regular transfusion requirement in regards to a rise in hemoglobin ≥1.0 g/dl and improvement in other parameters of hemolysis even with a low 50 mg twice daily dose. Minor adverse effects, including headache, insomnia, and nausea were reported.Subsequent adult studies like ACTIVATE III (non-transfusion-dependent) and ACTIVATE III – T (transfusion-dependent) in patients with PKD showed sustained hemoglobin response in 16/40 (40%) patients. It was tolerated well, and the adverse effect profile was similar to the previous study except for hypertriglyceridemia and hypertension in two patients.Phase I/II trials on patients with thalassemia and sickle cell anemia have also shown promising results in reducing transfusion burden and other disease-related co-morbidities, paving the way for further studies.Mitapivat appears to be a safe, well-tolerated, and effective drug for PKD and other RBC pathologies in adults. Results of ongoing pediatric studies in these settings are awaited to reveal its safety profile in children.

Switching from Deferasirox Dispersible Tablets to Deferasirox Film-Coated Tablets: Is There an Effect on Ferritin Levels in Children and Adolescents with Transfusion-Dependent Anemia?

To investigate the effect of switching from deferasirox dispersible tablet (DT) to deferasirox film-coated tablet (FCT) on serum ferritin (SF) levels in transfusion-dependent patients. Patients who received regular erythrocyte transfusion and whose treatment was switched from DT to FCT were included in the study. FCT start date was taken as the index date. Patients were followed over 2 equal and long periods, both before and after index date. Thirty-two patients were included, and the comparison periods ranged from 4 to 12 months. The SF values increased from a median of 1723 ng/mL (range 717-5369 ng/mL) to 1.853 ng/mL (range 924-5478 ng/mL) after switching from DT to FCT (P = .036). While there was a significant increase in median SF after switching in Turkish patients (1467 ng/mL to 1778 ng/ mL, P = .010) and patients ≥12 years (1598-1848 ng/mL, P = .009), there was an insignificant (P = .859) decrease in SF in immigrant children. Considering only the post-switch period, there was a non-significant increase in median SF in the entire cohort, while SF decreased significantly in immigrant children (P = .026). No serious side effects were observed in any patient that would cause discontinuation of treatment. Overall, higher SF value was observed with FCT compared to DT in short term. There were different results between patient groups. Our results suggest that FCT is more effective than DT in patients with high basal ferritin and who are actually incompatible with treatment and should be preferred first in these patients.

Aplastic Anaemia Associated with Bendamustine Therapy - A Rare Side Effect.

During treatment for malignant lymphoma, cytopenia can develop for several reasons. This can range from mild cytopenias leading to infection and bleeding to full-blown drug-induced aplastic anaemia. While aplastic anaemia affects individuals of all genders and ages, here, we describe aplastic anaemia after chemotherapy exposure to bendamustine in a 65-year-old female with non-Hodgkin's lymphoma. A 65-year-old woman with recurrent indolent marginal zone lymphoma and post-chemotherapy with bendamustine and rituximab, presented with a neutropenic fever and was admitted with a leading diagnosis of sepsis. In the previous two weeks, the patient required regular transfusions of packed red blood cells and platelets and maintained a daily ZARXIO® regimen. Laboratory results revealed pancytopenia, and broad-spectrum antibiotics (cefepime/vancomycin) were given. The patient was subsequently admitted to the hospital under the care of the haematology/oncology team and was ultimately diagnosed with aplastic anaemia, likely as a consequence of bendamustine chemoimmunotherapy. She elicited a positive response to the triple immunosuppressive therapy (IST) regimen (two immunotherapeutic agents plus one anti-thymocyte globulin (ATG), after which her cell counts returned to normal. This case underscores the importance of recognising haematologic complications linked to bendamustine and advocates for further research to increase the understanding among healthcare professionals of drug-induced aplastic anaemia. Bendamustine can cause severe autoimmune haemolytic anaemia and aplastic anaemia and may require multiple transfusions and a multidrug regimen for treatment. The use of ATG as a therapeutic intervention is appropriate because it has been effective in treating aplastic anaemia. Bendamustine can cause severe autoimmune haemolytic anaemia and aplastic anaemia, a side effect which has rarely been reported but is of significant clinical importance.Drug-induced aplastic anaemia is a complex, potentially devastating consequence of treating blood cancers and is a relatively unexplored area that requires further understanding.Anti-thymocyte globulin is effective in treating bendamustine-induced aplastic anaemia as it degrades lymphocytes that destroy the bone marrow.

Prognostic Role of Multiparametric Cardiac Magnetic Resonance in Neo Transfusion-Dependent Thalassemia.

We prospectively evaluated the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in non-transfusion-dependent β-thalassemia (β-NTDT) patients who started regular transfusions in late childhood/adulthood (neo β-TDT). We considered 180 patients (38.25 ± 11.24 years; 106 females). CMR was used to quantify cardiac iron overload, biventricular function, and atrial dimensions, and to detect left ventricular (LV) replacement fibrosis. During a mean follow-up of 76.87 ± 41.60 months, 18 (10.0%) cardiovascular events were recorded: 2 heart failures, 13 arrhythmias (10 supraventricular), and 3 cases of pulmonary hypertension. Right ventricular (RV) end-diastolic volume index (EDVI), RV mass index (MI), LV replacement fibrosis, and right atrial (RA) area index emerged as significant univariate prognosticators of cardiovascular complications. The low number of events prevented us from performing a multivariable analysis including all univariable predictors simultaneously. Firstly, a multivariable analysis including the two RV size parameters (mass and volume) was carried out, and only the RV MI was proven to independently predict cardiovascular diseases. Then, a multivariable analysis, including RV MI, RA atrial area, and LV replacement fibrosis, was conducted. In this model, RV MI and LV replacement fibrosis emerged as independent predictors of cardiovascular outcomes (RV MI: hazard ratio (HR) = 1.18; LV replacement fibrosis: HR = 6.26). Our results highlight the importance of CMR in cardiovascular risk stratification.